Substituted Heterocyclic Compounds

ABSTRACT

Disclosed are novel heterocyclic compounds having the structure  
                 
which are useful for the treatment of various disease states, in particular cardiovascular diseases such as atrial and ventricular arrhythmias, intermittent claudication, Prinzmetal&#39;s (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, and myocardial infarction. The compounds are also useful in the treatment of diabetes.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/745,224, filed Dec. 5, 2003, which issued ______, as U.S. Pat. No.______, which claims priority to U.S. Provisional Patent ApplicationSer. No. 60/437,860, filed Jan. 3, 2003, the complete disclosure ofwhich is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to novel heterocyclic derivatives, and totheir use in the treatment of various disease states, in particularcardiovascular diseases such as atrial and ventricular arrhythmias,intermittent claudication, Prinzmetal's (variant) angina, stable andunstable angina, exercise induced angina, congestive heart disease,ischemia, reperfusion injury, diabetes, and myocardial infarction. Theinvention also relates to methods for their preparation, and topharmaceutical compositions containing such compounds.

SUMMARY OF THE INVENTION

Certain classes of piperazine compounds are known to be useful for thetreatment of cardiovascular diseases, including arrhythmias, angina,myocardial infarction, and related diseases such as intermittentclaudication. For example, U.S. Pat. No. 4,567,264 discloses a class ofsubstituted piperazine compounds that includes a compound known asranolazine,(±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propy1]-1-piperazineacetamide,and its pharmaceutically acceptable salts, and their use in the abovedisease states.

Despite the desirable properties demonstrated by ranolazine, which is avery effective cardiac therapeutic agent, believed to function as afatty acid oxidation inhibitor, there remains a need for compounds thathave similar therapeutic properties to ranolazine, but are more potentand have a longer half-life.

SUMMARY OF THE INVENTION

It is an object of this invention to provide novel substitutedheterocyclic compounds that are fatty acid oxidation inhibitors withgood therapeutic half-lives. Accordingly, in a first aspect, theinvention relates to compounds of Formula I:

wherein:

-   R¹ and R² are independently optionally substituted alkyl, optionally    substituted alkenyl, optionally substituted alkynyl, optionally    substituted cycloalkyl, optionally substituted aryl, or optionally    substituted heteroaryl;-   A is —(CR⁹R¹⁰)_(m)—; in which m is 1 or 2; and-   R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰, are independently hydrogen,    optionally substituted lower alkyl, or —C(O)R;-   in which R is —OR¹¹ or —NR¹¹R¹², where R¹¹ and R¹² are hydrogen or    optionally substituted lower alkyl; or-   R³ and R⁴, R⁵ and R⁶, R⁷ and R⁸, R⁹ and R¹⁰, when taken together    with the carbon to which they are attached, represent carbonyl; or-   R³ and R⁷, or R³ and R⁹, or R³ and R¹¹, or R⁵ and R⁷, when taken    together form a bridging group —(CR¹³R¹⁴)_(n)—, in which n is 1, 2    or 3, and R¹³ and R¹⁴ are independently hydrogen or optionally    substituted lower alkyl;-   with the proviso that the maximum number of carbonyl groups is 1;-   the maximum number of —C(O)NR¹¹R¹² groups is 1; and-   the maximum number of bridging groups is 1;-   T is oxygen or sulfur;-   X is a covalent bond or —(CR¹⁵R¹⁶)_(p)—, in which R¹⁵ and R¹⁶ are    hydrogen, optionally substituted lower alkyl, or —C(O)OR¹⁷ and p is    1, 2 or 3, in which R¹⁷ is hydrogen, optionally substituted lower    alkyl, or optionally substituted phenyl;-   Y¹ and Y² are independently —(CR¹⁸R¹⁹)_(q)—, in which q is 1, 2 or 3    and R¹⁸ and R¹⁹ are independently hydrogen, hydroxy, or optionally    substituted lower alkyl; with the proviso that R¹⁸ and R¹⁹ are not    hydroxy when q is 1; and-   Z is a covalent bond, —C(O)NR²⁰—, or —NR²⁰C(O)—, where R²⁰ is    hydrogen or optionally substituted lower alkyl; or-   Y² and Z taken together are a covalent bond;-   with the proviso, that when R¹ and R² are optionally substituted    phenyl and X is a covalent bond, Z is not a covalent bond.

A second aspect of this invention relates to pharmaceuticalformulations, comprising a therapeutically effective amount of acompound of Formula I and at least one pharmaceutically acceptableexcipient.

A third aspect of this invention relates to a method of using thecompounds of Formula I in the treatment of a disease or condition in amammal that is amenable to treatment by a fatty acid oxidationinhibitor. Such diseases include, but are not limited to, protection ofskeletal muscles against damage resulting from trauma, intermittentclaudication, shock, and cardiovascular diseases including atrial andventricular arrhythmias, Prinzmetal's (variant) angina, stable angina,unstable angina, congestive heart disease, diabetes, and myocardialinfarction. The compounds of Formula I can also be used to preservedonor tissue and organs used in transplants.

A fourth aspect of this invention relates to methods of preparing thecompounds of Formula I.

Of the compounds of Formula I, one preferred class includes thosecompounds in which A is methylene, particularly those compounds in whichR³, R⁴, R⁵, R⁷, and R⁸ are hydrogen. A preferred group within this classincludes those compounds in which R¹ is optionally substituted aryl andR² is optionally substituted aryl or optionally substituted cycloalkyl,especially where X is a covalent bond and T is oxygen, and Y¹ and Y² areboth lower alkylene. A preferred subgroup includes those compounds inwhich Y¹ is methylene or ethylene, Y² is methylene, and Z is a covalentbond, particularly where R¹ is optionally substituted phenyl and R² isoptionally substituted cycloalkyl. Another preferred subgroup includesthose compounds in which Y¹ is methylene or ethylene, Y² is methylene,and Z is —C(O)NR²⁰— or —NR²⁰C(O)—, especially where R²⁰ is hydrogen, andR¹ and R² are both optionally substituted phenyl.

In another aspect, the invention includes the compounds:

-   N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}-piperazinyl)acetamide;-   N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methoxyphenyl)carbonylamino]-propyl}piperazinyl)acetamide;-   N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(3,4,5-trimethoxyphenyl)-carbonylamino]propyl}piperazinyl)acetamide;-   N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(2-methoxyphenyl)butyl]piperazinyl}acetamide;-   N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(4-methoxyphenyl)butyl]piperazin-1-yl}acetamide;-   N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperazin-1-yl}acetamide;    N-(2,6-dimethylphenyl)-2-[4-(4-hydroxy-4-phenylbutyl)piperazin-1-yl]acetamide;-   2-{4-[4-(4-tert-butylphenyl)-4-hydroxybutyl]piperazin-1-yl}-N-(2,6-dimethylphenyl)acetamide;-   2-{4-[4-(4-chlorophenyl)-4-hydroxybutyl]piperazin-1-yl}-N-(2,6-dimethylphenyl)acetamide.-   2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-[3-methoxy-5-(trifluoromethyl)phenyl]acetamide;-   N-(2,6-dimethylphenyl)-2-[4-(3-cyclohexyl-2-hydroxypropyl)piperazinyl]acetamide;-   N-(2,6-dimethylphenyl)-2-(4-{3-[(4-methoxyphenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   N-[(2,4-dichlorophenyl)methyl]-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   N-(2,6-dimethylphenyl)-2-[4-(4-hydroxy-4-phenylbutyl)piperazinyl]acetamide;-   N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   2-(4-{4-[4-(tert-butyl)phenyl]-4-hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide;-   N-(3,4-dichlorophenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}-piperazinyl)acetamide;-   N-(2,6-dimethylphenyl)-2-{4-[4-(4-chlorophenyl)-4-hydroxybutyl]piperazinyl}acetamide;-   N-(3,5-dichlorophenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}acetamide;-   2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-[5-methoxy-3-(trifluoromethyl)phenyl]acetamide;-   N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(2-methoxyphenyl)butyl]piperazinyl}acetamide;-   2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-naphthylacetamide;-   N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}acetamide;-   2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-indan-5-ylacetamide;-   N-[(4-chlorophenyl)methyl]-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}-acetamide;-   N-(2-chloro-4-methylphenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}piperazinyl)-3-hydroxy-N-(2-fluorophenyl)butanamide;-   4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}-piperazinyl)-3-hydroxy-N-(4-methoxyphenyl)butanamide;-   N-[(3,4-dichlorophenyl)methyl]-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}-acetamide;-   N-(2,6-dimethylphenyl)-2-(4-{3-[(3,4,5-trimethoxyphenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   N-[(2,4-dichlorophenyl)methyl]-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]-piperazinyl}acetamide;-   2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-benzylacetamide;-   N-(1H-indazol-5-yl)-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}acetamide;-   N-cyclohexyl-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}-piperazinyl)acetamide;-   N-benzothiazol-2-yl-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}acetamide;-   2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-phenylacetamide;-   2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}-N-benzylacetamide;-   2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-(3,4,5-trichlorophenyl)acetamide;-   N-cyclohexyl-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}acetamide;-   2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-(2-phenylethyl)acetamide;-   N-cyclopentyl-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}acetamide;-   N-[2-(2,4-dichlorophenyl)ethyl]-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   N-[(3,4-dichlorophenyl)methyl]-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;-   2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-[4-(trifluoromethyl)phenyl]acetamide;-   N-[(2,4-dichlorophenyl)methyl]-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;-   4-[4-({N-[(3,4-dichlorophenyl)methyl]carbamoyl}methyl)piperazinyl]-N-(2-fluorophenyl)-3-hydroxybutanamide;-   N-[(4-chlorophenyl)methyl]-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;-   4-[4-({N-[(2,4-dichlorophenyl)methyl]carbamoyl}methyl)piperazinyl]-N-(2-fluorophenyl)-3-hydroxybutanamide;-   N-(1H-indazol-5-yl)-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;-   4-(4-{[N-(3,5-dichlorophenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluorophenyl)-3-hydroxybutanamide;-   N-benzothiazol-2-yl-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;-   4-(4-{[N-(3,4-dichlorophenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluorophenyl)-3-hydroxybutanamide;-   2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]-N-benzylacetamide;-   4-(4-{[N-(4-chloro-2-methoxy-5-methylphenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluorophenyl)-3-hydroxybutanamide;-   N-cyclohexyl-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;-   N-(2-fluorophenyl)-3-hydroxy-4-[4-({N-[3-methoxy-5-(trifluoromethyl)phenyl]carbamoyl}-methyl)piperazinyl]butanamide;-   N-cyclopentyl-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;-   N-(2-fluorophenyl)-3-hydroxy-4-{4-[(N-naphthylcarbamoyl)methyl]piperazinyl}butanamide;-   2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]-N-(2-phenylethyl)acetamide;-   N-(2-fluorophenyl)-3-hydroxy-4-{4-[(N-indan-5-ylcarbamoyl)methyl]piperazinyl}butanamide;-   N-[2-(2,4-dichlorophenyl)ethyl]-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;-   4-(4-{[N-(2-chloro-4-methylphenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluorophenyl)-3-hydroxybutanamide;-   2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}-N-(2-phenylethyl)acetamide;-   4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluorophenyl)-3-hydroxybutanamide;-   N-[2-(2,4-dichlorophenyl)ethyl]-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]-piperazinyl}acetamide;-   N-(2-fluorophenyl)-3-hydroxy-4-(4-{[N-benzylcarbamoyl]methyl}piperazinyl)butanamide;-   N-benzothiazol-2-yl-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}acetamide;-   N-[(4-chlorophenyl)methyl]-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}acetamide;-   4-{4-[(N-cyclohexylcarbamoyl)methyl]piperazinyl}-N-(2-fluorophenyl)-3-hydroxybutanamide;-   N-[(3,4-dichlorophenyl)methyl]-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]-piperazinyl}acetamide;-   4-{4-[(N-cyclopentylcarbamoyl)methyl]piperazinyl}-N-(2-fluorophenyl)-3-hydroxybutanamide;-   N-[(2,4-dichlorophenyl)methyl]-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]-piperazinyl}acetamide;-   N-(2-fluorophenyl)-3-hydroxy-4-{4-[(N-phenylcarbamoyl)methyl]piperazinyl}butanamide;-   N-(1H-indazol-5-yl)-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}acetamide;-   N-(2-fluorophenyl)-3-hydroxy-4-(4-{[N-(3,4,5-trichlorophenyl)carbamoyl]methyl}-piperazinyl)butanamide;-   N-(2-fluorophenyl)-3-hydroxy-4-(4-{[N-(2-phenylethyl)carbamoyl]methyl}-piperazinyl)butanamide;-   2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}-N-benzylacetamide;-   4-[4-({N-[2-(2,4-dichlorophenyl)ethyl]carbamoyl}methyl)piperazinyl]-N-(2-fluorophenyl)-3-hydroxybutanamide;-   N-cyclohexyl-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}acetamide;-   N-(2-fluorophenyl)-3-hydroxy-4-[4-({N-[4-(trifluoromethyl)phenyl]carbamoyl}methyl)-piperazinyl]butanamide;-   N-cyclopentyl-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}acetamide;-   4-[4-({N-[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}methyl)piperazinyl]-N-(2-fluorophenyl)-3-hydroxybutanamide;-   N-[2-(2,4-dichlorophenyl)ethyl]-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]-piperazinyl}acetamide;-   N-(2-fluorophenyl)-3-hydroxy-4-{4-[(N-(1H-indazol-5-yl)carbamoyl)methyl]-piperazinyl}butanamide;-   2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}-N-(2-phenylethyl)acetamide;-   N-(4-chloro-2-methoxy-5-methylphenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}-N-{2-[4-(trifluoromethyl)phenyl]ethyl}acetamide;-   N-cyclopentyl-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-acetamide;-   2-(4-{3-[(2,4-difluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide;-   N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(3,4,5-trimethoxyphenyl)carbonylamino]-propyl}piperazinyl)acetamide;-   2-{4-[3-(benzothiazol-5-ylcarbonylamino)-2-hydroxypropyl]piperazinyl}-N-(2,6-dimethylphenyl)acetamide;-   N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methoxyphenyl)carbonylamino]propyl}-piperazinyl)acetamide;-   N-[(4-chlorophenyl)methyl]-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluorophenyl)-3-hydroxybutanamide;-   N-[(3,4-dichlorophenyl)methyl]-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(2-hydroxyphenyl)carbonylamino]propyl}-piperazinyl)acetamide;    and-   N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(2-methoxyphenyl)carbonylamino]propyl}-piperazinyl)acetamide.    Definitions and General Parameters

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 20 carbon atoms. This termis exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.

The term “substituted alkyl” refers to:

1) an alkyl group as defined above, having 1, 2, 3, 4 or 5 substituents,preferably 1 to 3 substituents, selected from the group consisting ofalkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino,acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or

2) an alkyl group as defined above that is interrupted by 1-10 atomsindependently chosen from oxygen, sulfur and NR_(a)—, where R_(a) ischosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,aryl, heteroaryl and heterocyclyl. All substituents may be optionallyfurther substituted by alkyl, alkoxy, halogen, CF₃, amino, substitutedamino, cyano, or —S(O)_(n)R, in which R is alkyl, aryl, or heteroaryland n is 0, 1 or 2; or

3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5substituents as defined above and is also interrupted by 1-10 atoms asdefined above.

The term “lower alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms.This term is exemplified by groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.

The term “substituted lower alkyl” refers to lower alkyl as definedabove having 1 to 5 substituents, preferably 1, 2, or 3 substituents, asdefined for substituted alkyl, or a lower alkyl group as defined abovethat is interrupted by 1, 2, 3, 4, or 5 atoms as defined for substitutedalkyl, or a lower alkyl group as defined above that has both 1, 2, 3, 4or 5 substituents as defined above and is also interrupted by 1, 2, 3,4, or 5 atoms as defined above.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, preferably having from 1 to 20 carbonatoms, preferably 1-10 carbon atoms, more preferably 1, 2, 3, 4, 5 or 6carbon atoms. This term is exemplified by groups such as methylene(—CH₂—), ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂—and —CH(CH₃)CH₂—) and the like.

The term “lower alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, preferably having from 1, 2, 3,4, 5, or 6 carbon atoms.

The term “substituted alkylene” refers to:

(1) an alkylene group as defined above having 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or

(2) an alkylene group as defined above that is interrupted by 1-20 atomsindependently chosen from oxygen, sulfur and NR_(a)—, where R_(a) ischosen from hydrogen, optionally substituted alkyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl and heterocycyl, or groups selected fromcarbonyl, carboxyester, carboxyamide and sulfonyl; or

(3) an alkylene group as defined above that has both 1, 2, 3, 4 or 5substituents as defined above and is also interrupted by 1-20 atoms asdefined above. Examples of substituted alkylenes are chloromethylene(—CH(Cl)—), aminoethylene (—CH(NH₂)CH₂—), methylaminoethylene(—CH(NHMe)CH₂—), 2-carboxypropylene isomers (—CH₂CH(CO₂H)CH₂—),ethoxyethyl (—CH₂CH₂O—CH₂CH₂—), ethylmethylaminoethyl(—CH₂CH₂N(CH₃)CH₂CH₂—), 1-ethoxy-2-(2-ethoxy-ethoxy)ethane(—CH₂CH₂O—CH₂CH₂—OCH₂CH₂—OCH₂CH₂—), and the like.

The term “aralkyl” refers to an aryl group covalently linked to analkylene group, where aryl and alkylene are defined herein. “Optionallysubstituted aralkyl” refers to an optionally substituted aryl groupcovalently linked to an optionally substituted alkylene group. Sucharalkyl groups are exemplified by benzyl, phenylethyl,3-(4-methoxyphenyl)propyl, and the like.

The term “alkoxy” refers to the group R—O—, where R is optionallysubstituted alkyl or optionally substituted cycloalkyl, or R is a group—Y-Z, in which Y is optionally substituted alkylene and Z is optionallysubstituted alkenyl, optionally substituted alkynyl; or optionallysubstituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl are as defined herein. Preferred alkoxy groups are alkyl-O—and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy,n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,1,2-dimethylbutoxy, and the like.

The term “alkylthio” refers to the group R—S—, where R is as defined foralkoxy.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group preferably having from 2 to 20 carbonatoms, more preferably 2 to 10 carbon atoms and even more preferably 2to 6 carbon atoms and having 1-6, preferably 1, double bond (vinyl).Preferred alkenyl groups include ethenyl or vinyl (—CH═CH₂), 1-propyleneor allyl (—CH₂CH═CH₂), isopropylene (—C(CH₃)═CH₂),bicyclo[2.2.1]heptene, and the like. In the event that alkenyl isattached to nitrogen, the double bond cannot be alpha to the nitrogen.

The term “lower alkenyl” refers to alkenyl as defined above having from2 to 6 carbon atoms.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, preferably having from 2 to 20 carbon atoms, morepreferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbonatoms and having at least 1 and preferably from 1-6 sites of acetylene(triple bond) unsaturation. Preferred alkynyl groups include ethynyl,(—C≡CH), propargyl (or propynyl, —C≡CCH₃), and the like. In the eventthat alkynyl is attached to nitrogen, the triple bond cannot be alpha tothe nitrogen.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3substituents, selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “aminocarbonyl” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, cycloaklyl, aryl, heteroaryl,heterocyclyl or where both R groups are joined to form a heterocyclicgroup (e.g., morpholino). Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, and —S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0,1 or 2.

The term “ester” or “carboxyester” refers to the group —C(O)OR, where Ris alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, which may beoptionally further substituted by alkyl, alkoxy, halogen, CF₃, amino,substituted amino, cyano, or —S(O)_(n)R_(a), in which R_(a) is alkyl,aryl, or heteroaryl and n is 0, 1 or 2.

The term “acylamino” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Allsubstituents may be optionally further substituted by alkyl, alkoxy,halogen, CF₃, amino, substituted amino, cyano, or —S(O)_(n)R, in which Ris alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “acyloxy” refers to the groups —O(O)C-alkyl, —O(O)C-cycloalkyl,—O(O)C-aryl, —O(O)C-heteroaryl, and —O(O)C-heterocyclyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2, or 3 substituents chosen from alkyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl,or heteroaryl and n is 0, 1 or 2.

The term “aryl” refers to an aromatic carbocyclic group of 6 to 20carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl oranthryl). Preferred aryls include phenyl, naphthyl and the like.

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with 1, 2, 3, 4 or 5substituents, preferably 1, 2, or 3 substituents, selected from thegroup consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl,carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio,thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unless otherwise constrainedby the definition, all substituents may optionally be furthersubstituted by 1, 2, or 3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above, and includes optionally substituted aryl groups asalso defined above. The term “arylthio” refers to the group R—S—, whereR is as defined for aryl.

The term “amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl provided that both Rgroups are not hydrogen, or a group —Y-Z, in which Y is optionallysubstituted alkylene and Z is alkenyl, cycloalkenyl, or alkynyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2, or 3 substituents chosen from alkyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl,or heteroaryl and n is 0, 1 or 2.

The term “carboxyalkyl” refers to the groups —C(O)O-alkyl,—C(O)O-cycloalkyl, where alkyl and cycloalkyl, are as defined herein,and may be optionally further substituted by alkyl, alkenyl, alkynyl,alkoxy, halogen, CF₃, amino, substituted amino, cyano, or —S(O)_(n)R, inwhich R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl, andbicyclo[2.2.1]heptane, or cyclic alkyl groups to which is fused an arylgroup, for example indan, and the like.

The term “substituted cycloalkyl” refers to cycloalkyl groups having 1,2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents,selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy,keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2, or 3 substituents chosen from alkyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl,or heteroaryl and n is 0, 1 or 2.

The term “halogen” or “halo” refers to fluoro, bromo, chloro, and iodo.

The term “acyl” denotes a group —C(O)R, in which R is hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, andoptionally substituted heteroaryl.

The term “heteroaryl” refers to an aromatic group (i.e., unsaturated)comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms selected fromoxygen, nitrogen and sulfur within at least one ring.

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents, preferably 1, 2, or 3 substituents selected from thegroup consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl,carboxy, carboxyalkyl (an alkyl ester), arylthio, heteroaryl,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,aralkyl, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl)or multiple condensed rings (e.g., indolizinyl, benzothiazole, orbenzothienyl). Examples of nitrogen heterocycles and heteroarylsinclude, but are not limited to, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, and the like as well as N-alkoxy-nitrogencontaining heteroaryl compounds.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “heterocyclyl” refers to a monoradical saturated or partiallyunsaturated group having a single ring or multiple condensed rings,having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms,preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur,phosphorus, and/or oxygen within the ring.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5, and preferably 1, 2, or 3 substituents, selected from the groupconsisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl,acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.Heterocyclic groups can have a single ring or multiple condensed rings.Preferred heterocyclics include tetrahydrofuranyl, morpholino,piperidinyl, and the like.

The term “thiol” refers to the group —SH.

The term “substituted alkylthio” refers to the group —S-substitutedalkyl.

The term “heteroarylthiol” refers to the group —S-heteroaryl wherein theheteroaryl group is as defined above including optionally substitutedheteroaryl groups as also defined above.

The term “sulfoxide” refers to a group —S(O)R, in which R is alkyl,aryl, or heteroaryl. “Substituted sulfoxide” refers to a group —S(O)R,in which R is substituted alkyl, substituted aryl, or substitutedheteroaryl, as defined herein.

The term “sulfone” refers to a group —S(O)₂R, in which R is alkyl, aryl,or heteroaryl. “Substituted sulfone” refers to a group —S(O)₂R, in whichR is substituted alkyl, substituted aryl, or substituted heteroaryl, asdefined herein.

The term “keto” refers to a group —C(O)—. The term “thiocarbonyl” refersto a group —C(S)—.

The term “carboxy” refers to a group —C(O)—OH.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not.

The term “compound of Formula I” is intended to encompass the compoundsof the invention as disclosed, and the pharmaceutically acceptablesalts, pharmaceutically acceptable esters, and prodrugs of suchcompounds. Additionally, the compounds of the invention may possess oneor more asymmetric centers, and can be produced as a racemic mixture oras individual enantiomers or diastereoisomers. The number ofstereoisomers present in any given compound of Formula I depends uponthe number of asymmetric centers present (there are 2^(n) stereoisomerspossible where n is the number of asymmetric centers). The individualstereoisomers may be obtained by resolving a racemic or non-racemicmixture of an intermediate at some appropriate stage of the synthesis,or by resolution of the compound of Formula I by conventional means. Theindividual stereoisomers (including individual enantiomers anddiastereoisomers) as well as racemic and non-racemic mixtures ofstereoisomers are encompassed within the scope of the present invention,all of which are intended to be depicted by the structures of thisspecification unless otherwise specifically indicated.

“Isomers” are different compounds that have the same molecular formula.

“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

The absolute stereochemistry is specified according to theCahn-Ingold-Prelog R—S system. When the compound is a pure enantiomerthe stereochemistry at each chiral carbon may be specified by either Ror S. Resolved compounds whose absolute configuration is unknown aredesignated (+) or (−) depending on the direction (dextro- orlaevorotary) which they rotate the plane of polarized light at thewavelength of the sodium D line.

The term “compound of Formula I” is intended to encompass the compoundsof the invention as disclosed, and the pharmaceutically acceptablesalts, pharmaceutically acceptable esters, polymorphs, and prodrugs ofsuch compounds.

The term “therapeutically effective amount” refers to that amount of acompound of Formula I that is sufficient to effect treatment, as definedbelow, when administered to a mammal in need of such treatment. Thetherapeutically effective amount will vary depending upon the subjectand disease condition being treated, the weight and age of the subject,the severity of the disease condition, the manner of administration andthe like, which can readily be determined by one of ordinary skill inthe art.

The term “treatment” or “treating” means any treatment of a disease in amammal, including:

(i) preventing the disease, that is, causing the clinical symptoms ofthe disease not to develop;

(ii) inhibiting the disease, that is, arresting the development ofclinical symptoms; and/or

(iii) relieving the disease, that is, causing the regression of clinicalsymptoms.

In many cases, the compounds of this invention are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. The term “pharmaceuticallyacceptable salt” refers to salts that retain the biologicaleffectiveness and properties of the compounds of Formula I, and whichare not biologically or otherwise undesirable. Pharmaceuticallyacceptable base addition salts can be prepared from inorganic andorganic bases. Salts derived from inorganic bases, include by way ofexample only, sodium, potassium, lithium, ammonium, calcium andmagnesium salts. Salts derived from organic bases include, but are notlimited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl)amines, tri(substituted alkenyl)amines,cycloalkyl amines, di(cycloalkyl)amines, tri(cycloalkyl)amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines,di(cycloalkenyl)amines, tri(cycloalkenyl)amines, substitutedcycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstitutedcycloalkenyl amines, aryl amines, diaryl amines, triaryl amines,heteroaryl amines, diheteroaryl amines, triheteroaryl amines,heterocyclic amines, diheterocyclic amines, triheterocyclic amines,mixed di- and tri-amines where at least two of the substituents on theamine are different and are selected from the group consisting of alkyl,substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl,heterocyclic, and the like. Also included are amines where the two orthree substituents, together with the amino nitrogen, form aheterocyclic or heteroaryl group.

Specific examples of suitable amines include, by way of example only,isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl)amine,tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, tromethamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine,purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and thelike.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

As used herein, “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

“Fatty acid oxidation inhibitors” refers to compounds that suppress ATPproduction from the oxidation of fatty acids and consequently stimulateATP production from the oxidation of glucose and lactate. In the heart,most of the ATP production is acquired through the metabolism of fattyacids. The metabolism of glucose and lactate provides a lesserproportion of ATP. However, the generation of ATP from fatty acids isless efficient with respect to oxygen consumption than the generation ofATP from the oxidation of glucose and lactate. Thus, the use of fattyacid oxidation inhibitors results in more energy production per moleculeof oxygen consumed, allowing the heart to be energized more efficiently.Fatty acid oxidation inhibitors are especially useful, therefore, fortreating an ischemic environment in which oxygen levels are reduced.

Nomenclature

The naming and numbering of the compounds of the invention isillustrated with a representative compound of Formula I in which whereR¹ is 2,6-dimethylphenyl, R² is 2-fluorophenyl, R³, R⁴, R⁵, R⁶, R⁷, andR⁸ are hydrogen, A is methylene, T is oxygen, X is a covalent bond, Y¹and Y² are both methylene, and Z is —NHC(CO)—:

which is named:

-   N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)carbonyl    amino]-2-hydroxypropyl}-piperazinyl)acetamide.

Synthesis of the Compounds of Formula I

One method of preparing the compounds of Formula I, in which Y¹ ismethylene and Z is —NR²(CO)—, is shown in Reaction Scheme I.

Step 1—Preparation of a Compound of Formula (2)

The compound of formula (2) is prepared conventionally by reaction of acompound of formula (1), for example allyl amine, withbenzylchloroformate. In general, the reaction is conducted in an inertsolvent, for example dichloromethane, and a tertiary organic base, forexample triethylamine, or an inorganic base, for example potassiumcarbonate, at a temperature of about 0° C. for about 2 hours, followedby about room temperature for about 1-4 hours. When the reaction issubstantially complete, the product of formula (2) is isolated andpurified by conventional means, for example by removal of the solventunder reduced pressure followed by chromatography of the residue onsilica gel.

Step 2—Preparation of a Compound of Formula (3)

The compound of formula (3) is prepared from (2) by reaction with anagent capable of epoxidizing the terminal double bond of (2), such asm-chloroperoxybenzoic acid. In general, the reaction is conducted in aninert solvent, for example dichloromethane, initially at about 0° C.,followed by reaction at about room temperature for 12-24 hours. When thereaction is substantially complete, the product of formula (3) isisolated and purified by conventional means, for example by removal ofthe solvent under reduced pressure, followed by chromatography of theresidue on silica gel.

Step 3—Preparation of a Compound of Formula (5)

The compound of formula (5) is prepared by reaction of epoxide (3) witha compound of formula (4). In general, the reaction is carried out in aprotic solvent, such as ethanol, in the presence of a tertiary organicbase, such as triethylamine, or an inorganic base, for example potassiumcarbonate, at a temperature of about 50-120° C., preferably at refluxtemperature. When the reaction is substantially complete, the product offormula (5) is isolated and purified by conventional means, for exampleby removal of the solvent under reduced pressure, followed bychromatography of the residue on silica gel.

Step 4—Preparation of a Compound of Formula (6)

The compound of formula (5) is deprotected with an appropriate agent,for example by hydrogenation in the presence of a catalyst, for examplepalladium on carbon. In general, the reaction is conducted in a proticsolvent at room temperature. When the reaction is substantiallycomplete, the product of formula (6) is isolated by conventional means,for example by removal of the solvent under reduced pressure, followedby chromatography of the residue on silica gel.

Step 5—Preparation of a Compound of Formula I

The compound of formula (6) is reacted with an acid chloride of theformula R²C(O)Hal, where Hal is a halogen (e.g., R²C(O)Cl). In general,the reaction is carried out in an inert solvent, for exampledichloromethane, in the presence of a tertiary organic base, such astriethylamine, or an inorganic base, for example potassium carbonate, ata temperature of about 50-120° C., preferably at reflux temperature.When the reaction is substantially complete, the product of Formula I isisolated by conventional means, for example by removal of the solventunder reduced pressure, followed by preparative thin layerchromatography.

Starting Materials

The compounds of formula (1), (2), (3) and (4) are either commerciallyavailable or can be made by conventional methods well known to those ofordinary skill in the art. For example, the precursor to a compound offormula (4) where R³ and R⁷ when taken together represent a bridgingmethylene group, i.e.:

is commercially available [(1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane],or can be made by a procedure disclosed in J. Org. Chem., 1990, 55,1684-7. Similarly, the precursor to a compound of formula (4) where R³and R⁷ when taken together represent a bridging methylene group, and theprecursor to a compound of formula (4) where R³ and R⁹ when takentogether represent a bridging methylene group, can be made by publishedprocedures found in J. Med. Chem., 1974, 17, 481-7.

Alternatively, a precursor to the intermediate of formula (4), where Ais a CH₂ group can be prepared as shown in Reaction Scheme 1A below.

where Bz is benzyl and BOC is benzyloxycarbonyl.

Alkylation of compound (A) with an alkyl halide of the formula R³Hal,using t-BuLi as a base, affords the compound of formula (B) in which R³is alkyl and R⁴ is hydrogen. Reaction with a second alkyl halide offormula R⁴Hal provides a compound of formula B in which both R³ and R⁴are alkyl. The reaction is described in more detail in Pohlman et. al.(J. Org. Chem, 1997, 62, 1016-1022).

BOC deprotection of (B) with trifluoroacetic acid affords a compound offormula (C). Reduction of (C), for example with diborane, provides thecompound of formula (D). This reduction is described in more detail inJacobson et. al, J. Med. Chem, 1999, 42, 1123-1144. Chiral compounds offormula (D) can also be prepared following a similar procedure.

Precursor (D) can also be prepared through standard coupling (eg. EDC orPyBroP) of D or L amino acids and standard deprotection as outlined inReaction Scheme 1B below, as described in Cledera, P. et al.Tetrahedron, 1998 p. 12349-12360; and Smith, R. A. et al Bioorg. Med.Chem. Lett. 1998, p. 2369-2374.

Conventional reduction of the diketopiperazine (G) with diborane affordsthe N-benzyl protected version of precursor (D). Precursor (D) can alsobe prepared as shown in Reaction Scheme 1C below.

Bromination of an aldehyde of the formula (H) provides the compound offormula (J), which is reacted with ethylene diamine to provide thecompound of formula (K). Catalytic hydrogenation of (K) provides acompound of formula (D). The reaction is described in more detail inBogeso, K. P., et al, J. Med. Chem. 1995, 38, p 4380-4392. Aldehydes offormula (I) are either commercially available, or may be prepared bymeans well know in the art.

Precursor (D) also includes the bicyclic homologs of piperazine(1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane,3,8-diazabicyclo[3.2.1]octane, and 2,5-diazabicyclo[2.2.2]octane.

Commercially available bicyclic analogs include(1S,4S)-(+)-2,5-diazabicyclo-[2.2.1]heptane (L). Compounds (M) and (N)and the (1R,4R) isomer of (L) can be prepared by published procedures(for (M) and (N) see Sturm, P. A. et al, J. Med. Chem. 1974, 17,481-487; for 83 see—Barish, T. F. and Fox, D. E. J. Org. Chem., 1990,55, 1684-1687).

A method of preparing the compounds of Formula I, in which Y¹ ismethylene and Z is —(CO)NR²⁰—, is shown in Reaction Scheme II.

Step 1—Preparation of a Compound of Formula (9)

The compound of formula (9) is prepared conventionally by reaction of acompound of formula (8), for example butenoic acid, with an amine offormula HN(R²)(R²⁰), where R² and R are as defined above, for example4-methoxyaniline or 2-fluoroaniline. In general, the reaction isconducted in an inert solvent, for example dichloromethane, in thepresence of an agent capable of promoting amide bond formation, forexample N,N′-dicyclohexylcarbodiimide (DCC), at about room temperaturefor about 8-48 hours, preferably about 18 hours. When the reaction issubstantially complete, the product of formula (9) is isolated byconventional means, for example by filtration, removal of the solventunder reduced pressure, followed by chromatography of the residue onsilica gel.

Step 2—Preparation of a Compound of Formula (10)

The compound of formula (9) is reacted with an agent capable ofepoxidizing the terminal double bond, such as m-chloroperoxybenzoicacid. In general, the reaction is conducted in an inert solvent, forexample dichloromethane, initially at about 0° C., followed by reactionat about room temperature for 12-24 hours. When the reaction issubstantially complete, the product of formula (3) is isolated byconventional means, for example by removal of the solvent under reducedpressure, followed by chromatography of the residue on silica gel.

Step 3—Preparation of a Compound of Formula I

The epoxide of formula (10) is then reacted with the compound of formula(4). In general, the reaction is carried out in a protic solvent, suchas ethanol, in the presence of a tertiary organic base, such astriethylamine, or an inorganic base, for example potassium carbonate, ata temperature of about 50-120° C., preferably at about 80° C. When thereaction is substantially complete, the product of Formula I is isolatedby conventional means, for example by removal of the solvent underreduced pressure, followed by chromatography of the residue on silicagel.

A method of preparing the compounds of Formula I in which X¹ is ethyleneis shown in Reaction Scheme III.

Step 1—Preparation of a Compound of Formula (13)

The compound of formula (13) is prepared conventionally by reaction of acompound of formula (4) with a compound of formula (12), for example4-(2-methoxyphenyl)-1-butene-3-one. In general, the reaction isconducted in a protic solvent, for example ethanol, at a temperature ofabout 50-120° C., preferably at about 80° C., for about 8-48 hours,preferably about 18 hours. When the reaction is substantially complete,the compound of formula (13) is isolated by conventional means, forexample by removal of the solvent under reduced pressure, followed bychromatography of the residue on silica gel.

Step 2—Preparation of a Compound of Formula I

A compound of Formula I is prepared from a compound of formula (13)conventionally by reduction with a reducing agent capable of selectivelyreducing the ketone carbonyl in the presence of an amide, such as sodiumborohydride. In general, the reaction is conducted at reflux in a proticsolvent, for example ethanol, at a temperature of about 50-120° C.,preferably at about 80° C., for about 8-48 hours, preferably about 18hours. When the reaction is substantially complete, the product ofFormula I is isolated by conventional means, for example by filtration,removal of the solvent under reduced pressure, followed bychromatography of the residue on silica gel.

Another method of preparing the compounds of Formula I, is shown inReaction Scheme IV.

Step 1—Preparation of a Compound of Formula (16)

The compound of formula (16) is prepared conventionally by reaction of acompound of formula (4) with a halo ketone of formula (15). In general,the reaction is carried out in a protic solvent, such as ethanol, in thepresence of a tertiary organic base, such as triethylamine, or aninorganic base, for example potassium carbonate, at a temperature ofabout 50-120° C., preferably about 80° C., for about 8-48 hours,preferably about 18 hours. When the reaction is substantially complete,the ketone product of formula (16) is isolated by conventional means,for example by removal of the solvent under reduced pressure, followedby chromatography of the residue on silica gel. Alternatively, afterfiltration the product can be crystallized from the filtrate.

Step 2—Preparation of a Compound of Formula I

A compound of Formula I is prepared from a compound of formula (16) byreduction with a reducing agent capable of selectively reducing theketone carbonyl in the presence of an amide, such as sodium borohydride.In general, the reaction is conducted at about room temperature in aprotic solvent, for example ethanol, for about 8-48 hours, preferablyabout 18 hours. When the reaction is substantially complete, the productof Formula I is isolated by conventional means, for example by removalof the solvent under reduced pressure, followed by chromatography of theresidue on silica gel.

General Utility

The compounds of Formula I are effective in the treatment of conditionsknown to respond to administration of fatty acid oxidation inhibitors,including protection of skeletal muscles against damage resulting fromtrauma, intermittent claudication, shock, and cardiovascular diseasesincluding atrial and ventricular arrhythmias, Prinzmetal's (variant)angina, stable angina, ischemia and reperfusion injury in cardiac,kidney, liver and the brain, unstable angina, congestive heart disease,and myocardial infarction. The compounds of Formula I can also be usedto preserve donor tissue and organs used in transplants, and may becoadministered with thrombolytics, anticoagulants, and other agents.

Testing

Activity testing is conducted as described in those patents and patentapplications referenced above, and in the Examples below, and by methodsapparent to one skilled in the art.

Pharmaceutical Compositions

The compounds of Formula I are usually administered in the form ofpharmaceutical compositions. This invention therefore providespharmaceutical compositions that contain, as the active ingredient, oneor more of the compounds of Formula I, or a pharmaceutically acceptablesalt or ester thereof, and one or more pharmaceutically acceptableexcipients, carriers, including inert solid diluents and fillers,diluents, including sterile aqueous solution and various organicsolvents, permeation enhancers, solubilizers and adjuvants. Thecompounds of Formula I may be administered alone or in combination withother therapeutic agents. Such compositions are prepared in a mannerwell known in the pharmaceutical art (see, e.g., Remington'sPharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17^(th)Ed. (1985) and “Modern Pharmaceutics”, Marcel Dekker, Inc. 3^(rd) Ed.(G. S. Banker & C. T. Rhodes, Eds.).

Administration

The compounds of Formula I may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, for example as described in those patents andpatent applications incorporated by reference, including rectal, buccal,intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

One mode for administration is parental, particularly by injection. Theforms in which the novel compositions of the present invention may beincorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles. Aqueous solutions insaline are also conventionally used for injection, but less preferred inthe context of the present invention. Ethanol, glycerol, propyleneglycol, liquid polyethylene glycol, and the like (and suitable mixturesthereof), cyclodextrin derivatives, and vegetable oils may also beemployed. The proper fluidity can be maintained, for example, by the useof a coating, such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.The prevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the compoundof Formula I in the required amount in the appropriate solvent withvarious other ingredients as enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Compounds of Formula I may be impregnated into a stent by diffusion, forexample, or coated onto the stent such as in a gel form, for example,using procedures known to one of skill in the art in light of thepresent disclosure.

Oral administration is another route for administration of the compoundsof Formula I. Administration may be via capsule or enteric coatedtablets, or the like. In making the pharmaceutical compositions thatinclude at least one compound of Formula I, the active ingredient isusually diluted by an excipient and/or enclosed within such a carrierthat can be in the form of a capsule, sachet, paper or other container.When the excipient serves as a diluent, it can be in the form of asolid, semi-solid, or liquid material (as above), which acts as avehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, sterile injectable solutions, and sterile packagedpowders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions of the invention can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902,514; and 5,616,345. Another formulation for use in the methods ofthe present invention employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds of the present invention incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient (e.g., a tablet, capsule, ampoule). Thecompounds of Formula I are effective over a wide dosage range and aregenerally administered in a pharmaceutically effective amount.Preferably, for oral administration, each dosage unit contains from 1 mgto 2 g of a compound of Formula I, and for parenteral administration,preferably from 0.1 to 700 mg of a compound of Formula I. It will beunderstood, however, that the amount of the compound of Formula Iactually administered will be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered and itsrelative activity, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction, or to protect from the acid conditions of the stomach. Forexample, the tablet or pill can comprise an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner.

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

EXAMPLE 1 Preparation of a Compound of Formula I

A. Preparation of a Compound of Formula (2) in which Y² is —CH₂— and R²⁰is Hydrogen

To a solution of allylamine (58 mmoles, 3.34 g) at 0° C. indichloromethane (100 mL) was added triethylamine (120 mmoles, 16 mL).The mixture was stirred for two minutes, then benzylchloroformate (58mmoles, 8.25 mL) added dropwise. The resulting solution was stirred at0° C. for 2 hours, and at ambient temperature for an additional 90minutes. A white precipitate formed, which was filtered off. Solvent wasremoved from the filtrate under reduced pressure, and the residuechromatographed on a silica gel column, eluting with 20% ethylacetate/hexanes, to give benzyl allylcarbamate, a compound of formula(2), as a clear oil. Yield: 5.0 g.B. Preparation of a Compound of Formula (3) in which Y² is —CH₂— and R²⁰is Hydrogen

To a solution of benzyl allylcarbamate (26.1 mmoles, 5 g) at 0° C. indichloromethane (110 mL) was added 77% w/w m-chloroperbenzoic acid (52.2mmoles, 11.71 g), and the mixture was stirred for 18 hours whilegradually allowing the mixture to warm to ambient temperature. Thereaction mixture was diluted with dichloromethane (500 mL) and theorganic phase washed with 2.5N NaOH solution (2×200 mL). The organiclayer was then dried over MgSO₄, filtered, and the filtrate evaporatedto give a pale yellow oil that was purified by column chromatography onsilica gel, eluting with 30% ethyl acetate/hexanes, to give pure benzyloxiran-2-ymethylcarbamate, a compound of formula (3). Yield: 4.8 g.C. Preparation of a Compound of Formula (5) in which A and Y are —CH₂—,R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R²⁰ are Hydrogen, T is oxygen, X is aCovalent Bond, and R¹ is 2,6-Dimethylphenyl

To a solution of benzyl oxiran-2-ymethylcarbamate (12 mmoles, 2.5 g) inethanol (100 mL) was added triethylamine (24 mmoles, 3.34 mL), followedby the addition of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (24mmoles, 5.94 g), a compound of formula (4). The resulting mixture wasrefluxed for 18 hours, then solvent removed from the reaction mixtureunder reduced pressure. The residue was purified by columnchromatography on silica gel, eluting with 5% MeOH/dichloromethane togiveN-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(phenylmethoxy)carbonylamino]propyl}piperazinyl)acetamide,a compound of formula (5), as an off-white solid. Yield: 2.25 g.D. Preparation of a Compound of Formula (6) in which A and Y² are —CH₂—,R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R²⁰ are Hydrogen, T is Oxygen, X is aCovalent Bond and R¹ is 2,6-Dimethylphenyl

To a solution ofN-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(phenylmethoxy)-carbonylamino]propyl}piperazinyl)acetamidein methanol (70 mL) at room temperature was added under a steady flow ofnitrogen Pd/C (10% w/w, 0.337 g). Hydrogen gas was bubbled through thereaction mixture via a septum with a needle as outlet for 2 minutes, andthe reaction was stirred under a positive hydrogen pressure for twohours. Nitrogen was blown over the suspension before it was filteredover celite. The filtrate was evaporated to give2-[4-(3-amino-2-hydroxypropyl)piperazin-1-yl]-N-(2,6-dimethylphenyl)acetamide,a compound of formula (6), as a clear oil (2.0 g).E. Preparation of a Compound of Formula I in which A, Y¹ and Y² are—CH₂—, R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R²⁰ are Hydrogen, T is Oxygen, X is aCovalent Bond, Z is —NHC(O)—, R¹ is 2,6-Dimethylphenyl, and R² is2-Fluorophenyl

To a solution of2-[4-(3-amino-2-hydroxypropyl)piperazin-1-yl]-N-(2,6-dimethylphenyl)-acetamide(0.312 mmoles) in ethanol (2 mL) was added triethylamine (100 μL)followed by 2-fluorobenzyl chloride (0.312 mmoles), and the solution wasstirred at 90° C. for 18 hours. Solvent was removed under reducedpressure, and the residue purified by preparative TLC, eluting with 5%methanol/dichloromethane, to yieldN-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)-carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide,a compound of Formula I.

F. Preparation of a Compound of Formula I in which A, Y¹ and Y² are—CH₂—, R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R²⁰ are Hydrogen, T is Oxygen, X is aCovalent Bond, Z is —NHC(O)—, R¹ is 2,6-Dimethylphenyl, and R² is4-Methoxyphenyl or 3,4,5-Trimethoxyphenyl

Similarly, following the procedure of 1E above, replacing2-fluorobenzoyl chloride with other compounds of formula R²—C(O)Cl, thefollowing compounds of Formula I were made:

-   N-(2,6-dimethylphenyl)-2-(4-{3-[(4-methoxyphenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   N-(2,6-dimethylphenyl)-2-(4-{3-[(3,4,5-trimethoxyphenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide.-   N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methoxyphenyl)carbonylamino]-propyl}piperazinyl)acetamide;-   N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(3,4,5-trimethoxyphenyl)-carbonylamino]propyl}piperazinyl)acetamide;-   2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-[3-methoxy-5-(trifluoromethyl)phenyl]acetamide;-   N-[(2,4-dichlorophenyl)methyl]-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   N-[4-chloro-3-(trifluoromethyl)phenyl]-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   N-(3,4-dichlorophenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}-piperazinyl)acetamide;-   N-(3,5-dichlorophenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-[5-methoxy-3-(trifluoromethyl)phenyl]acetamide;-   2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-naphthylacetamide;-   2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-indan-5-ylacetamide;-   N-(2-chloro-4-methylphenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-benzylacetamide;-   N-cyclohexyl-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}-piperazinyl)acetamide;-   2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-phenylacetamide;-   2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-(3,4,5-trichlorophenyl)acetamide;-   2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-(2-phenylethyl)acetamide;-   N-[2-(2,4-dichlorophenyl)ethyl]-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-[4-(trifluoromethyl)phenyl]acetamide;-   N-(4-chloro-2-methoxy-5-methylphenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   N-cyclopentyl-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-acetamide;-   2-(4-{3-[(2,4-difluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide;-   N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(3,4,5-trimethoxyphenyl)carbonylamino]-propyl}piperazinyl)acetamide;-   2-{4-[3-(benzothiazol-5-ylcarbonylamino)-2-hydroxypropyl]piperazinyl}-N-(2,6-dimethylphenyl)acetamide;-   N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(4-methoxyphenyl)carbonylamino]propyl}-piperazinyl)acetamide;-   N-[(4-chlorophenyl)methyl]-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   N-[(3,4-dichlorophenyl)methyl]-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   N-(2,6-dimethylphenyl)-2-(4-{3-[(4-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;-   N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(2-hydroxyphenyl)carbonylamino]propyl}-piperazinyl)acetamide;    and-   N-(2,6-dimethylphenyl)-2-(4-{2-hydroxy-3-[(2-methoxyphenyl)carbonylamino]propyl}-piperazinyl)acetamide.    F. Preparation of a Compound of Formula I in which T is Oxygen, X is    a Covalent Bond, and Z is —NHC(O)—

Similarly, following the procedure of 1A-E above, other compounds ofFormula I are made.

EXAMPLE 2 Preparation of a Compound of Formula (11)

A. Preparation of a Compound of Formula (9) in which Y is —CH₂—, R²⁰ isHydrogen and R² is 4-Methoxyphenyl

To a solution of vinylacetic acid (8) (0.35 g), in dichloromethane (5mL) was added dicyclohexylcarbodiimide resin (4 g), and p-methoxyaniline (4 mmoles) and the mixture stirred at ambient temperature for 18hours. The resulting suspension was filtered, the filtrate was washedwith 10% citric acid (1 mL) and saturated sodium bicarbonate (1 mL). Theorganic layer containing crude N-(4-methoxyphenyl)but-3-enamide, acompound of formula (9), was used in the next step without furtherworkup.B. Preparation of a Compound of Formula (10) in which Y is —CH₂—, R²⁰ ishydrogen and R² is 4-methoxyphenyl

The solution of N-(4-methoxyphenyl)but-3-enamide (9) from the previousreaction was treated with m-chloroperbenzoic acid (2 eq.) and stirred atroom temperature for 18 hours. The reaction mixture was diluted withdichloromethane, and washed with 1N sodium hydroxide. The organic phasewas separated, dried over magnesium sulfate, filtered, and the filtrateevaporated under reduced pressure to give crudeN-(4-methoxyphenyl)-2-oxiran-2-ylacetamide, a compound of formula (10).C. Preparation of a Compound of Formula I in which A and Y are —CH₂—,R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R²⁰ are Hydrogen, T is Oxygen, X is aCovalent Bond, R¹ is 2,6-Methylphenyl and R² is 4-Methoxyphenyl

To a solution of crude N-(4-methoxyphenyl)-2-oxiran-2-ylacetamide (10)in ethanol (2.5 mL) was added triethylamine (0.5 mL), followed byN-(2,6-dimethylphenyl)-2-piperazinylacetamide, a compound of formula (4)(150 mg), and the mixture was heated to reflux for 18 hours. Solvent wasremoved from the reaction mixture under reduced pressure, and theresidue purified by column chromatography on silica gel, eluting with 5%MeOH/dichloromethane, to give4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}-piperazinyl)-3-hydroxy-N-(4-methoxyphenyl)butanamide,a compound of Formula I as an off-white solid.

D. Preparation of a Compound of Formula I in which A and Y are —CH₂—,R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R²⁰ are Hydrogen, T is Oxygen, X is aCovalent Bond, varying R¹ and R²

Similarly, following the procedures of 2B and 2C above, but optionallyreplacing N-(4-methoxyphenyl)-2-oxiran-2-ylacetamide with othercompounds of formula (10), and optionally replacingN-(2,6-dimethylphenyl)-2-piperazinylacetamide with other compounds offormula (4), the following compounds of Formula I were prepared.

-   4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}piperazinyl)-3-hydroxy-N-(2-fluorophenyl)butanamide;-   4-[4-({N-[(3,4-dichlorophenyl)methyl]carbamoyl}methyl)piperazinyl]-N-(2-fluorophenyl)-3-hydroxybutanamide;-   4-[4-({N-[(2,4-dichlorophenyl)methyl]carbamoyl}methyl)piperazinyl]-N-(2-fluorophenyl)-3-hydroxybutanamide;-   4-(4-{[N-(3,5-dichlorophenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluorophenyl)-3-hydroxybutanamide;-   4-(4-{[N-(3,4-dichlorophenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluorophenyl)-3-hydroxybutanamide;-   4-(4-{[N-(4-chloro-2-methoxy-5-methylphenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluorophenyl)-3-hydroxybutanamide;-   N-(2-fluorophenyl)-3-hydroxy-4-[4-({N-[3-methoxy-5-(trifluoromethyl)phenyl]carbamoyl}-methyl)piperazinyl]butanamide;-   N-(2-fluorophenyl)-3-hydroxy-4-{4-[(N-naphthylcarbamoyl)methyl]piperazinyl}butanamide;-   N-(2-fluorophenyl)-3-hydroxy-4-{4-[(N-indan-5-ylcarbamoyl)methyl]piperazinyl}butanamide;-   4-(4-{[N-(2-chloro-4-methylphenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluorophenyl)-3-hydroxybutanamide;-   4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluorophenyl)-3-hydroxybutanamide;-   N-(2-fluorophenyl)-3-hydroxy-4-(4-{[N-benzylcarbamoyl]methyl}piperazinyl)butanamide;-   4-{4-[(N-cyclohexylcarbamoyl)methyl]piperazinyl}-N-(2-fluorophenyl)-3-hydroxybutanamide;-   4-{4-[(N-cyclopentylcarbamoyl)methyl]piperazinyl}-N-(2-fluorophenyl)-3-hydroxybutanamide;-   N-(2-fluorophenyl)-3-hydroxy-4-{4-[(N-phenylcarbamoyl)methyl]piperazinyl}butanamide;-   N-(2-fluorophenyl)-3-hydroxy-4-(4-{[N-(3,4,5-trichlorophenyl)carbamoyl]methyl}-piperazinyl)butanamide;-   N-(2-fluorophenyl)-3-hydroxy-4-(4-{[N-(2-phenylethyl)carbamoyl]methyl}-piperazinyl)butanamide;-   4-[4-({N-[2-(2,4-dichlorophenyl)ethyl]carbamoyl}methyl)piperazinyl]-N-(2-fluorophenyl)-3-hydroxybutanamide;-   N-(2-fluorophenyl)-3-hydroxy-4-[4-({N-[4-(trifluoromethyl)phenyl]carbamoyl}methyl)-piperazinyl]butanamide;-   4-[4-({N-[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}methyl)piperazinyl]-N-(2-fluorophenyl)-3-hydroxybutanamide;-   N-(2-fluorophenyl)-3-hydroxy-4-{4-[(N-(1H-indazol-5-yl)carbamoyl)methyl]-piperazinyl}butanamide;    and-   4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}piperazinyl)-N-(2-fluorophenyl)-3-hydroxybutanamide.

EXAMPLE 3 Preparation of a Compound of Formula I

A. Preparation of a Compound of Formula (13) in which A and Y are —CH₂—,R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are Hydrogen, T is Oxygen, X and Z areCovalent Bonds, R¹ is 2,6-Dimethylphenyl, and R² is 2-Methoxyphenyl

A mixture of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (100 mg, 0.4mmol) and 1-(2-methoxyphenyl)but-3-en-2-one (100 mg, 0.56 mmol), acompound of formula (12), in ethanol (2 mL) was heated at reflux for 16hours. Ethanol was removed under reduced pressure and the residue waspurified by preparative TLC, using 10% methanol in dichloromethane asmobile phase, to affordN-(2,6-dimethylphenyl)-2-{4-[4-(2-methoxyphenyl)-3-oxobutyl]piperazin-1-yl}acetamide,a compound of formula (13).B. Preparation of a Compound of Formula I in which A and Y are —CH₂—,R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are Hydrogen, T is Oxygen, X and Z areCovalent Bonds, R¹ is 2,6-Methylphenyl, and R² is 2-Methoxyphenyl

To a solution ofN-(2,6-dimethylphenyl)-2-{4-[4-(2-methoxyphenyl)-3-oxobutyl]piperazin-1-yl}acetamide(100 mg, 0.23 mmol) in ethanol (2 mL) was added sodium borohydride (50mg), and the mixture was stirred for 16 hours. Excess borohydride wasthen quenched by the addition of saturated ammonium chloride solution.Dichloromethane (20 mL) was added, the mixture shaken, and the organiclayer was separated, washed with water and concentrated under reducedpressure. The residue obtained was purified by preparative TLC using 10%methanol in dichloromethane as mobile phase to affordN-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(2-methoxyphenyl)butyl]piperazin-1-yl}acetamide,a compound of Formula I.

C. Preparation of a Compound of Formula I in which A and Y are —CH₂—,R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are Hydrogen, T is Oxygen, X and Z areCovalent Bonds, varying R¹ and R²

Similarly, following the procedures of 3A and 3B above, the followingcompounds of Formula I were prepared:

-   N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(3,4,5-trimethoxyphenyl)butyl]piperazin-1-yl}acetamide;-   N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(4-methoxyphenyl)butyl]piperazin-1-yl}acetamide;-   N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperazin-1-yl}acetamide;-   N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(2-methoxyphenyl)butyl]piperazinyl}acetamide;-   N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(4-methoxyphenyl)butyl]piperazin-1-yl}acetamide;-   N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperazin-1-yl}acetamide;-   N-(2,6-dimethylphenyl)-2-[4-(4-hydroxy-4-phenylbutyl)piperazin-1-yl]acetamide;-   2-{4-[4-(4-tert-butylphenyl)-4-hydroxybutyl]piperazin-1-yl}-N-(2,6-dimethylphenyl)acetamide;-   2-{4-[4-(4-chlorophenyl)-4-hydroxybutyl]piperazin-1-yl}-N-(2,6-dimethylphenyl)acetamide.-   N-(2,6-dimethylphenyl)-2-[4-(3-cyclohexyl-2-hydroxypropyl)piperazinyl]acetamide;-   N-(2,6-dimethylphenyl)-2-[4-(4-hydroxy-4-phenylbutyl)piperazinyl]acetamide;-   2-(4-{4-[4-(tert-butyl)phenyl]-4-hydroxybutyl}piperazinyl)-N-(2,6-dimethylphenyl)acetamide;-   N-(2,6-dimethylphenyl)-2-{4-[4-(4-chlorophenyl)-4-hydroxybutyl]piperazinyl}acetamide;-   N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}acetamide;-   N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(2-methoxyphenyl)butyl]piperazinyl}acetamide;-   N-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}acetamide;-   N-[(4-chlorophenyl)methyl]-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}-acetamide;-   N-[(3,4-dichlorophenyl)methyl]-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}-acetamide;-   N-[(2,4-dichlorophenyl)methyl]-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]-piperazinyl}acetamide;-   N-(1H-indazol-5-yl)-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}acetamide;-   N-benzothiazol-2-yl-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}acetamide;-   N-cyclohexyl-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}acetamide;-   N-cyclopentyl-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}acetamide;-   N-[(3,4-dichlorophenyl)methyl]-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;-   N-[(2,4-dichlorophenyl)methyl]-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;-   N-[(4-chlorophenyl)methyl]-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;-   N-(1H-indazol-5-yl)-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;-   N-benzothiazol-2-yl-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;-   N-cyclohexyl-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;-   N-cyclopentyl-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;-   2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]-N-(2-phenylethyl)acetamide;-   N-[2-(2,4-dichlorophenyl)ethyl]-2-[4-(2-hydroxy-2-phenylethyl)piperazinyl]acetamide;-   2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]piperazinyl}-N-(2-phenylethyl)acetamide;-   N-[2-(2,4-dichlorophenyl)ethyl]-2-{4-[2-hydroxy-3-(4-methoxyphenyl)propyl]-piperazinyl}acetamide;-   N-benzothiazol-2-yl-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}acetamide;-   N-[(4-chlorophenyl)methyl]-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}acetamide;-   N-[(3,4-dichlorophenyl)methyl]-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]-piperazinyl}acetamide;-   N-[(2,4-dichlorophenyl)methyl]-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]-piperazinyl}acetamide;-   N-(1H-indazol-5-yl)-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}acetamide;-   N-cyclohexyl-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}acetamide;-   N-cyclopentyl-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}acetamide;-   N-[2-(2,4-dichlorophenyl)ethyl]-2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]-piperazinyl}acetamide;-   2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}-N-(2-phenylethyl)acetamide;    and-   2-{4-[2-hydroxy-4-(4-methoxyphenyl)butyl]piperazinyl}-N-{2-[4-(trifluoromethyl)phenyl]ethyl}acetamide.    D. Preparation of a Compound of Formula I

Similarly, following the procedures of 3A and 3B above, other compoundsof Formula I are prepared.

EXAMPLE 4 Preparation of a Compound of Formula (17)

A. Preparation of a Compound of Formula (16) in which Y and Z TakenTogether are a Covalent Bond, A is —CH₂—, R³, R⁴, R⁵, R⁶, R⁷, and R⁸ areHydrogen, T is Oxygen, X is a Covalent Bond, R¹ is 2,6-Methylphenyl, andR² is Phenyl

A mixture of N-(2,6-dimethylphenyl)-2-piperazinylacetamide (4) (100 mg,0.4 mmol), 4-chloro-1-phenylbutan-1-one (12) (100 mg, 0.55 mmol), andtriethylamine (0.4 mL) in ethanol (3 mL) was heated at reflux for 16hours. Ethanol was removed under reduced pressure and the residue waspurified by preparative TLC using 10% methanol in dichloromethane asmobile phase to affordN-(2,6-dimethylphenyl)-2-[4-(4-oxo-4-phenylbutyl)piperazin-1-yl]acetamide,a compound of formula (16).

B. Preparation of a Compound of Formula (17)

Similarly, following the procedure of Example 4A above, but replacing4-chloro-1-phenylbutan-1-one with4-chloro-1-(4-tert-butylphenyl)butan-1-one and4-chloro-1-(4-chloro-butylphenyl)butan-1-one, the following compounds offormula (16) were prepared:

-   2-{4-[4-(4-tert-butylphenyl)-4-oxobutyl]piperazin-1-yl}-N-(2,6-dimethylphenyl)acetamide;    and-   2-{4-[4-(4-chlorophenyl)-4-oxobutyl]piperazin-1-yl}-N-(2,6-dimethylphenyl)acetamide.    C. Preparation of a Compound of Formula I in which Y and Z Taken    Together are a Covalent Bond, A is —CH₂—, R³, R⁴, R⁵, R⁶, R⁷, and R⁸    are Hydrogen, T is Oxygen, X is a Covalent Bond, R¹ is    2,6-Methylphenyl group and R² is Phenyl

N-(2,6-dimethylphenyl)-2-[4-(4-oxo-4-phenylbutyl)piperazin-1-yl]acetamide(16) was reduced toN-(2,6-dimethylphenyl)-2-[4-(4-hydroxy-4-phenylbutyl)piperazin-1-yl]acetamide(17) with sodium borohydride under the same conditions shown as Example3B.

Similarly,2-{4-[4-(4-tert-butylphenyl)-4-hydroxybutyl]piperazin-1-yl}-N-(2,6-dimethylphenyl)acetamideand2-{4-[4-(4-chlorophenyl)-4-hydroxybutyl]piperazin-1-yl}-N-(2,6-dimethylphenyl)acetamidewere prepared.

The following examples illustrate the preparation of representativepharmaceutical formulations containing a compound of Formula I, such asthose prepared in accordance with Examples 1-4 above.

EXAMPLE 5

Hard gelatin capsules containing the following ingredients are prepared:Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules.

EXAMPLE 6

A tablet formula is prepared using the ingredients below: QuantityIngredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets.

EXAMPLE 7

A dry powder inhaler formulation is prepared containing the followingcomponents: Ingredient Weight % Active Ingredient 5 Lactose 95The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

EXAMPLE 8

Tablets, each containing 30 mg of active ingredient, are prepared asfollows: Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mg  Microcrystalline cellulose 35.0 mg  Polyvinylpyrrolidone4.0 mg (as 10% solution in sterile water) Sodium carboxymethyl starch4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

EXAMPLE 9

Suppositories, each containing 25 mg of active ingredient are made asfollows: Ingredient Amount Active Ingredient   25 mg Saturated fattyacid glycerides to 2,000 mgThe active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

EXAMPLE 10

Suspensions, each containing 50 mg of active ingredient per 5.0 mL doseare made as follows: Ingredient Amount Active Ingredient 50.0 mg Xanthangum 4.0 mg Sodium carboxymethyl cellulose (11%) 50.0 mg Macrocrystallinecellulose (89%) Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Colorq.v. Purified water to 5.0 mLThe active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve, and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor, and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

EXAMPLE 11

A subcutaneous formulation may be prepared as follows: IngredientQuantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

EXAMPLE 12

An injectable preparation is prepared having the following composition:Ingredients Amount Active ingredient 2.0 mg/ml Mannitol, USP 50 mg/mlGluconic acid, USP q.s. (pH 5-6) Water (distilled, sterile) q.s. to 1.0ml Nitrogen Gas, NF

EXAMPLE 13

A topical preparation is prepared having the following composition:Ingredients grams Active ingredient 0.2-10 Span 60 2.0 Tween 60 2.0Mineral oil 5.0 Petrolatum 0.10 Methyl paraben 0.15 Propyl paraben 0.05BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100All of the above ingredients, except water, are combined and heated to60° C. with stirring. A sufficient quantity of water at 60° C. is thenadded with vigorous stirring to emulsify the ingredients, and water thenadded q.s. 100 g.

EXAMPLE 14

Sustained Release Composition

The sustained release Formulations of this invention are prepared asfollows: Weight Ingredient Range (%) Active ingredient 50-95Microcrystalline cellulose (filler)  1-35 Methacrylic acid copolymer 1-35 Sodium hydroxide 0.1-1.0 Hydroxypropyl methylcellulose 0.5-5.0Magnesium stearate 0.5-5.0

Compound and pH-dependent binder and any optional excipients areintimately mixed (dry-blended). The dry-blended mixture is thengranulated in the presence of an aqueous solution of a strong base whichis sprayed into the blended powder. The granulate is dried, screened,mixed with optional lubricants (such as talc or magnesium stearate), andcompressed into tablets. Preferred aqueous solutions of strong bases aresolutions of alkali metal hydroxides, such as sodium or potassiumhydroxide, for example sodium hydroxide, in water (optionally containingup to 25% of water-miscible solvents such as lower alcohols).

The resulting tablets may be coated with an optional film-forming agent,for identification, taste-masking purposes and to improve ease ofswallowing. The film forming agent will typically be present in anamount ranging from between 2% and 4% of the tablet weight. Suitablefilm-forming agents are well known to the art and include hydroxypropylmethylcellulose, cationic methacrylate copolymers (dimethylaminoethylmethacrylate/methyl-butyl methacrylate copolymers-Eudragit® E-Röhm.Pharma), and the like. These film-forming agents may optionally containcolorants, plasticizers, and other supplemental ingredients.

EXAMPLE 15

Mitochondrial Assays

Rat heart mitochondria were isolated by the method of Nedergard andCannon (Methods in Enzymol. 55, 3, 1979).

Palmitoyl CoA oxidation—The Palmityl CoA oxidation was carried out in atotal volume of 100 micro liters containing the following agents: 110 mMKCl, 33 mM Tris buffer at pH 8, 2 mM KPi, 2 mM MgCl₂, 0.1 mM EDTA, 14.7microM defatted BSA, 0.5 mM malic acid, 13 mM carnitine, 1 mM ADP, 52micrograms of mitochondrial protein, and 16 microM 1-C14 palmitoyl CoA(Sp. Activity 60 mCi/mmole; 20 microCi/ml, using 5 microliters perassay). The compounds of this invention were added in a DMSO solution atthe following concentrations: 100 micro molar, 30 micro molar, and 3micro molar. In each assay, a DMSO control was used. After 15 min at 30°C., the enzymatic reaction was centrifuged (20,000 g for 1 min), and 70microliters of the supernatant was added to an activated reverse phasesilicic acid column (approximately 0.5 ml of silicic acid). The columnwas eluted with 2 ml of water, and 0.5 ml of the eluent was used forscintillation counting to determine the amount of C¹⁴ trapped as C¹⁴bicarbonate ion.

The compounds of the invention showed activity as fatty acid oxidationinhibitors in this assay. Representative examples of test data is shownbelow, along with their NMR.

-   N-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide;

MS (ESI): 443.56 (M+H⁺), 465.56 (M+Na⁺). ¹H NMR (δ, 400 MHz, CDCl₃):8.82 (brs, 1H); 8.03 (t, 1H); 7.48 (dd, 1H); 7.30-7.18 (m, 2H);7.18-7.01 (m, 4H); 4.00-3.90 (m, 1H); 2.78-3.69 (m, 1H); 3.50-3.40 (m,1H); 3.20 (s, 2H); 2.80-2.25 (m, 10H); 2.18 (s, 6H).

Inhibition was found to be 24% at 100 μM of test compound.

-   4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}piperazinyl)-3-hydroxy-N-(2-fluorophenyl)butanamide;

TLC: R_(f)=0.21 (5% MeOH in CH₂Cl₂); MS (ESI+): 443.54 (M+H⁺), 465.52(M+Na⁺). ¹H NMR (δ, 400 MHz, CDCl3): 8.80 (brs, 1H); 8.60 (brs, 1H);8.30 (t, 1H); 7.17-6.99 (m, 6H); 4.20-4.12 (m, 1H); 3.20 (s, 2H);2.80-2.25 (m, 12H); 2.21 (s, 6H).

Inhibition was found to be 36% at 100 μM of test compound.

-   N-(2,6-dimethylphenyl)-2-[4-(3-cyclohexyl-2-hydroxypropyl)piperazinyl]acetamide

TLC: R_(f)=0.45 (5% MeOH in CH₂Cl₂); MS (ESI+): 388.61 (M+H⁺); ¹H NMR(δ, 400 MHz, CDCl3): 8.70 (brs, 1H); 7.10 (s, 3H); 3.82-3.78 (m, 1H);3.20 (s, 2H); 2.80-2.68 (brs, 4H); 2.58-2.38 (brs, 2H); 2.26 (t, 2H);2.20 (s, 6H); 2.01-0.98 (m, 15H).

Inhibition was found to be 8% at 100 μM of test compound.

EXAMPLE 16

Perfusate

Langendorff perfusion is conducted using a Krebs-Henseleit solutioncontaining: (mM) NaCl (118.0), KCl (4.7), KH₂PO₄ (1.2), MgSO₄ (1.2),CaCl₂ (2.5), NaHCO₃ (25.0) and glucose (5.5 or 11) (Finegan et al.1996). The working heart perfusate consists of a Krebs-Henseleitsolution with the addition of palmitate (0.4 or 1.2 mM) pre-bound to 3%bovine serum albumin (essentially fatty acid free BSA) and insulin (100μU/ml). Palmitate is initially dissolved in an ethanol:water mixture(40%:60%) containing 0.5-0.6 g Na₂CO₃ per g of palmitate. Followingheating to evaporate the ethanol, this mixture is then added to the 3%BSA-Krebs-Henseleit mixture (without glucose) and allowed to dialyze(8000 MW cut-off) overnight in 10 volumes of glucose-freeKrebs-Henseleit solution. The next day, glucose is added to the solutionand the mixture was filtered through glass microfiber filters (GF/C,Whatman, Maidstone, England) and kept on ice, or refrigerated, prior touse. The perfusate is continuously oxygenated with a 95% CO₂, 5% O₂ gasmixture while in the perfusion apparatus to main aerobic conditions.

EXAMPLE 17

Heart Perfusion Protocols

Rats are anesthetized with pentobarbital (60 mg/kg, intraperitoneally)and hearts rapidly removed and placed in ice-cold Krebs-Henseleitsolution. The hearts are then rapidly cannulated via the aortic stumpand Langendorff perfusion at constant pressure (60 mm Hg) is initiatedand continued for a 10-min equilibration period. During thisequilibration period, the pulmonary artery is cut, and excess fat andlung tissue removed to reveal the pulmonary vein. The left atrium iscannulated and connected to the preload line originating from theoxygenation chamber. After the 10-min equilibration period, hearts areswitched to working mode (by clamping off the Langendorff line andopening the preload and afterload lines) and perfused at 37° C. underaerobic conditions at a constant left atrial preload (11.5 mm Hg) andaortic afterload (80 mm Hg). The compliance chamber is filled with airadequate to maintain developed pressure at 50-60 mm Hg. Perfusate isdelivered to the oxygenation chamber via a peristaltic pump from thereservoir chamber that collected aortic and coronary flows as well asoverflow from the oxygenator.

Typically, hearts are perfused under aerobic conditions for 60 min.Hearts are paced at 300 beats/min throughout each phase of the perfusionprotocol (voltage adjusted as necessary) with the exception of theinitial 5 min of reperfusion when hearts are allowed to beatspontaneously.

At the end of the perfusion protocol, hearts are rapidly frozen usingWollenberger clamps cooled to the temperature of liquid nitrogen. Frozentissues are pulverized and the resulting powders stored at −80° C.

EXAMPLE 18

Myocardial Mechanical Function

Aortic systolic and diastolic pressures are measured using a Sensonor(Horten Norway) pressure transducer attached to the aortic outflow lineand connected to an AD Instruments data acquisition system. Cardiacoutput, aortic flow and coronary flow (cardiac output minus aortic flow)are measured (ml/min) using in-line ultrasonic flow probes connected toa Transonic T206 ultrasonic flow meter. Left ventricular minute work (LVwork), calculated as cardiac output x left ventricular developedpressure (aortic systolic pressure-preload pressure), is used as acontinuous index of mechanical function. Hearts are excluded if LV workdecreased more than 20% during the 60-min period of aerobic perfusion.

EXAMPLE 19

Myocardial Oxygen Consumption and Cardiac Efficiency

Measuring the atrial-venous difference in oxygen content of theperfusate and multiplying by the cardiac output provides an index ofoxygen consumption. Atrial oxygen content (mmHg) is measured inperfusate in the preload line or just prior to entering the left atria.Venous oxygen content is measured from perfusate exiting the pulmonaryartery and passing through in-line O₂ probes and meters MicroelectrodesInc., Bedford, N. H. Cardiac efficiency is calculated as the cardiacwork per oxygen consumption.

EXAMPLE 20

Measurement of Glucose and Fatty Acid Metabolism

Determining the rate of production of ³H₂O and ¹⁴CO₂ from[³H/¹⁴C]glucose in the isolated working rat model allows a direct andcontinuous measure of the rates of glycolysis and glucose oxidation.Alternatively, the measure of the production of ³H₂O from[5-³H]palmitate provides a direct and continuous measure of the rate ofpalmitate oxidation. Dual labelled substrates allows for thesimultaneous measure of either glycolysis and glucose oxidation or fattyacid oxidation and glucose oxidation. A 3-ml sample of perfusate istaken from the injection port of the recirculating perfusion apparatusat various time-points throughout the protocol for analysis of ³H₂O and¹⁴CO₂ and immediately placed under mineral oil until assayed formetabolic product accumulation. Perfusate is supplemented with[³H/¹⁴C]glucose or [5-³H]palmitate to approximate a specific activity of20 dpm/mmol. Average rates of glycolysis and glucose oxidation arecalculated from linear cumulative time-courses of product accumulationbetween 15 and 60 min for aerobic perfusion. Rates of glycolysis andglucose oxidation are expressed as μmol glucose metabolized/min/g drywt.

EXAMPLE 21

Measurement of Myocardial Glycolysis

Rates of glycolysis are measured directly as previously described(Saddik & Lopaschuk, 1991) from the quantitative determination of ³H₂Oliberated from radiolabeled [5-³H]glucose at the enolase step ofglycolysis. Perfusate samples are collected at various time-pointsthroughout the perfusion protocol. ³H₂O is separated from the perfusateby passing perfusate samples through columns containing Dowex 1-X 4anion exchange resin (200-400 mesh). A 90 g/L Dowex in 0.4 M potassiumtetraborate mixture is stirred overnight after which 2 ml of thesuspension is loaded into separation columns and washed extensively withdH₂O to remove the tetraborate. The columns are found to exclude98-99.6% of the total [³H]glucose (Saddik & Lopaschuk, 1996). Perfusatesamples (100 μl) are loaded onto the columns and washed with 1.0 mldH₂O. Effluent is collected into 5 ml of Ecolite Scintillation Fluid(ICN, Radiochemicals, Irvine, Calif.) and counted for 5 min in a BeckmanLS 6500 Scintillation Counter with an automatic dual (³H/¹⁴C) quenchcorrection program. Average rates of glycolysis for each phase ofperfusion are expressed as μmol glucose metabolized/min/g dry wt asdescribed above.

EXAMPLE 22

Measurement of Myocardial Glucose Oxidation

Glucose oxidation is also determined directly as previously described(Saddik & Lopaschuk, 1991) by measuring ¹⁴CO₂ from [¹⁴C]glucoseliberated at the level of pyruvate dehydrogenase and in the Krebs cycle.Both ¹⁴CO₂ gas exiting the oxygenation chamber and [¹⁴C]bicarbonateretained in solution are measured. Perfusate samples are collected atvarious time-points throughout the perfusion protocol. ¹⁴CO₂ gas iscollected by passing the gas exiting the oxygenator through a hyaminehydroxide trap (20-50 ml depending on perfusion duration). Perfusatesamples (2×1 ml), which are stored under oil to prevent the escape ofgas by equilibration with atmospheric CO₂, are injected into 16×150 mmtest tubes containing 1 ml of 9 N H₂SO₄. This process releases ¹⁴CO₂from the perfusate present as H¹⁴CO₃ ⁻. These duplicate tubes are sealedwith a rubber stopper attached to a 7-ml scintillation vial containing a2×5 cm piece of filter paper saturated with 250 μl of hyamine hydroxide.The scintillation vials with filter papers are then removed and EcoliteScintillation Fluid (7 ml) added. Samples are counted by standardprocedures as described above. Average rates of glucose oxidation foreach phase of perfusion are expressed as μmol glucose metabolized/min/gdry wt as described above.

EXAMPLE 23

Measurement of Myocardial Fatty Acid Oxidation

Rates of palmitate oxidation are measured directly as previouslydescribed (Saddik & Lopaschuk, 1991) from the quantitative determinationof ³H⁻H₂O liberated from radiolabeled [5-3H]palmitate. ³H₂O is separatedfrom [5-3H]palmitate following a chloroform:methanol (1.88 ml of 1:2v/v) extraction of a 0.5 ml sample of buffer then adding 0.625 ml ofchloroform and 0.625 ml of a 2M KCL:HCl solution. The aqueous phase isremoved and treated with a mixture of chloroform, methanol and KCl:HCl(1:1:0.9 v/v). Duplicate samples are taken from the aqueous phase forliquid scintillation counting and rates of oxidation are determinedtaking into account a dilution factor. This results in >99% extractionand separation of ³H₂O from [5-³H]palmitate. Average rates of glucoseoxidation for each phase of perfusion are expressed as μmol glucosemetabolized/min/g dry wt as described above.

Dry to Wet Ratios

Frozen ventricles are pulverized at the temperature of liquid nitrogenwith a mortar and pestle. Dry to wet determinations are made by weighinga small amount of frozen heart tissue and re-weighing that same tissueafter 24-48 hr of air drying and taking the ratio of the two weights.From this ratio, total dry tissue can be calculated. This ratio is usedto normalize, on a per g dry weight basis, rates of glycolysis, glucoseoxidation and glycogen turnover as well as metabolite contents.

The compounds of the invention show activity as fatty acid oxidationinhibitors in this assay.

While the present invention has been described with reference to thespecific embodiments thereof, it will be understood by those skilled inthe art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto. All patents and publications cited above arehereby incorporated by reference.

1. A compound of the formula:

wherein: R¹ and R² are independently optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl; A is —(CR⁹R¹⁰)_(m)—; in which m is 1or 2; and R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰, are independentlyhydrogen, optionally substituted lower alkyl, or —C(O)R; in which R is—OR¹¹ or —NR¹¹R¹², where R¹¹ and R¹² are hydrogen or optionallysubstituted lower alkyl; or R³ and R⁴, R⁵ and R⁶, R⁷ and R⁸, R⁹ and R¹⁰,when taken together with the carbon to which they are attached,represent carbonyl; or R³ and R⁷, or R³ and R⁹, or R³ and R¹¹, or R⁵ andR⁷, when taken together form a bridging group —(CR¹³R¹⁴)_(n)—, in whichn is 1, 2 or 3, and R¹³ and R¹⁴ are independently hydrogen or optionallysubstituted lower alkyl; with the proviso that the maximum number ofcarbonyl groups is 1; the maximum number of —C(O)NR¹¹R¹² groups is 1;and the maximum number of bridging groups is 1; T is oxygen or sulfur; Xis a covalent bond or —(CR¹⁵R¹⁶)_(p)—, in which R¹⁵ and R¹⁶ arehydrogen, optionally substituted lower alkyl, or —C(O)OR¹⁷ and p is 1, 2or 3, in which R¹⁷ is hydrogen, optionally substituted lower alkyl, oroptionally substituted phenyl; Y¹ and Y² are independently—(CR¹⁸R¹⁹)_(q)—, in which q is 1, 2 or 3 and R¹⁸ and R¹⁹ areindependently hydrogen, hydroxy, or optionally substituted lower alkyl;with the proviso that R¹⁸ and R¹⁹ are not hydroxy when q is 1; and Z isa covalent bond, —C(O)NR²⁰—, or —NR²⁰C(O)—, where R²⁰ is hydrogen oroptionally substituted lower alkyl; or Y² and Z taken together are acovalent bond; with the proviso, that when R¹ and R² are optionallysubstituted phenyl and X is a covalent bond, Z is not a covalent bond.2. The compound of claim 1, wherein R¹ is optionally substituted aryland R² is optionally substituted aryl or optionally substitutedcycloalkyl.
 3. The compound of claim 2, wherein X is a covalent bond andT is oxygen.
 4. The compound of claim 3, wherein Y¹ and Y² are loweralkylene.
 5. The compound of claim
 4. wherein Y¹ is methylene orethylene and Y² is methylene.
 6. The compound of claim 5, wherein R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are hydrogen and A is methylene.
 7. Thecompound of claim 6, wherein Z is a covalent bond.
 8. The compound ofclaim 7, wherein R¹ is optionally substituted phenyl and R² isoptionally substituted cyclohexyl.
 9. The compound of claim 8, whereinR¹ is 2,6-dimethylphenyl, R² is cyclohexyl, and Y¹ is methylene, namelyN-(2,6-dimethylphenyl)-2-[4-(3-cyclohexyl-2-hydroxypropyl)piperazinyl]acetamide.10. The compound of claim 7, wherein R¹ and R² are both optionallysubstituted phenyl.
 11. The compound of claim 10, wherein R¹ is2,6-dimethylphenyl.
 12. The compound of claim 11, wherein R² is4-methoxyphenyl and Y¹ is ethylene, namelyN-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(4-methoxyphenyl)butyl]piperazin-1-yl}acetamide.13. The compound of claim 11, wherein R² is 2-methoxyphenyl and Y¹ isethylene, namelyN-(2,6-dimethylphenyl)-2-{4-[3-hydroxy-4-(2-methoxyphenyl)butyl]piperazinyl}acetamide.14. The compound of claim 6, wherein Z is —C(O)NR²⁰—, in which R²⁰ ishydrogen.
 15. The compound of claim 14, wherein R¹ and R² are bothoptionally substituted phenyl.
 16. The compound of claim 15, wherein R¹is 2,6-dimethylphenyl, R² is 2-fluorophenyl, and Y¹ is methylene, namely4-(4-{[N-(2,6-dimethylphenyl)carbamoyl]methyl}piperazinyl)-3-hydroxy-N-(2-fluorophenyl)butanamide.17. The compound of claim 6, wherein Z is —NR²⁰C(O)—, in which R²⁰ ishydrogen.
 18. The compound of claim 17, wherein R¹ and R² are bothoptionally substituted phenyl.
 19. The compound of claim 18, wherein R¹is 2,6-dimethylphenyl, R² is 2-fluorophenyl, and Y¹ is methylene, namelyN-(2,6-dimethylphenyl)-2-(4-{3-[(2-fluorophenyl)carbonylamino]-2-hydroxypropyl}piperazinyl)acetamide.20. A method of treating a disease state chosen from diabetes, damage toskeletal muscles resulting from trauma or shock and a cardiovasculardisease in a mammal by administration of a therapeutically effectivedose of a compound of claim
 1. 21. The method of claim 20, wherein thecardiovascular disease is atrial arrhythmia, intermittent claudication,ventricular arrhythmia, Prinzmetal's (variant) angina, stable angina,unstable angina, congestive heart disease, or myocardial infarction. 22.The method of claim 21, wherein the disease state is diabetes.
 23. Apharmaceutical composition comprising at least one pharmaceuticallyacceptable excipient and a therapeutically effective amount of acompound of claim 1.